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摘要： MDM2 inhibitors are promising therapeutics for acute myeloid leukemia (AML) with wild-type TP53. Through an integrated analysis of functional genomic data from primary patient samples, we found that an MDM2 inhibitor, idasanutlin, like venetoclax, is ineffective against monocytic leukemia (French-American-British [FAB] subtype M4/M5). To dissect the underlying resistance mechanisms, we explored both intrinsic and extrinsic factors. We found that monocytic leukemia cells express elevated levels of CEBPB, which promote monocytic differentiation, suppress CASP3 and CASP6, and upregulate MCL1, BCL2A1, and the interleukin (IL-1)/tumor necrosis factor alpha (TNF-alpha)/NF-kappa B pathway members, thereby conferring drug resistance to a broad range of MDM2 inhibitors, BH3 mimetics, and venetoclax combinations. In addition, aberrant monocytes in M4/M5 leukemia produce elevated levels of IL-1 and TNF-alpha, which promote monocytic differentiation and upregulate inflammatory cytokines and receptors, thereby extrinsically protecting leukemia blasts from venetoclax and MDM2 inhibition. Interestingly, IL-1 beta and TNF-alpha only increase CEBPB levels and protect M4/M5 cells from these drugs but not M0/M1 leukemia cells. Treatment with venetoclax and idasanutlin induces compensatory upregulation of CEBPB and the IL-1/TNF-alpha/NF-kappa B pathway independent of the FAB subtype, indicating drug-induced compensatory protection mechanisms. The combination of venetoclax or idasanutlin with inhibitors that block the IL-1/TNF-alpha pathway demonstrates synergistic cytotoxicity in M4/M5 AML. As such, we uncovered a targetable positive feedback loop that involves CEBPB, IL-1/TNF-alpha, and monocyte differentiation in M4/M5 leukemia and promotes both intrinsic and extrinsic drug resistance and drug-induced protection against venetoclax and MDM2 inhibitors.

关键词： 结直肠癌   肝转移   环状RNA   竞争性内源RNA   免疫浸润  

摘要： 结直肠癌是全球第三大常见癌症，其肝转移显著影响患者预后，本研究通过生物信息学手段构建基于circRNA的竞争性内源RNA（Competing endogenous RNA， ceRNA）网络，探讨其在结直肠癌肝转移中的作用及与免疫浸润的相关性，并寻找潜在的生物标志物。从GEO数据库下载无肝转移和肝转移结直肠癌患者的原位组织基因表达数据，使用R包筛选差异表达基因，包括circRNA， miRNA和mRNA，并通过CSCD数据库预测circRNA-miRNA相互作用，结合miRTarBase和TargetScan数据库预测miRNA-mRNA互作，利用Cytoscape 3.8.0构建ceRNA网络。利用Metascape对差异表达的mRNA进行功能富集分析，并对核心基因进行免疫浸润分析，探索ceRNA网络调控肿瘤进程的免疫机制，最后通过TCGA数据库验证关键基因的表达水平与结直肠癌肝转移的相关性。共筛选出差异表达的109个circRNA，114个miRNA，104个mRNA，构建了含有差异表达的5个circRNA，5个miRNA和4个mRNA的ceRNA网络。GO和KEGG富集分析显示，该网络中mRNA主要参与白细胞活化调节和免疫反应路径。免疫浸润分析表明，4个节点基因的表达水平均与免疫浸润分数呈正相关，其中主要组织相容性复合体II类DR α (Major Histocompatibility Complex， Class II， DR Alpha， HLA-DRA)与其相关性最强。TCGA数据库的进一步验证结果显示HLA-DRA高表达时结直肠癌肝转移率低。本研究提示HLA-DRA可能是预测结直肠癌肝转移的潜在生物标志物，可能为其临床诊断和未来分子靶向药物的开发提供方向。

关键词： 重症肺炎合并呼吸衰竭   高迁移率族蛋白B1   白细胞介素-17   病情进展   预后  

摘要： 目的：探讨血清高迁移率族蛋白B1（HMGB1）、白细胞介素-17（IL-17）水平对重症肺炎合并呼吸衰竭患者病情进展及预后的预测价值。方法：选取2021年2月至2024年2月陕西省结核病防治院118例重症肺炎合并呼吸衰竭患者，根据病情分为轻度组（n=40）、中度组（n=58）和重度组（n=20）。另选择同期110例健康体检者为对照组。根据患者预后结局分为生存组（n=89）和死亡组（n=29）。比较不同预后患者临床资料及血清HMGB1、IL-17水平，并分析血清HMGB1、IL-17水平与临床相关指标的相关性；分析患者预后影响因素，并评估血清HMGB1、IL-17水平对预后的预测价值。结果：与轻度组相比，中度、重度组血清HMGB1、IL-17水平明显升高（P<0.05），重度组血清HMGB1、IL-17水平明显高于中度组（P<0.05）；死亡组中性粒细胞及血清IL-6、IFN-γ、PCT、CRP、HMGB1和IL-17水平高于生存组（P<0.05）；血清HMGB1、IL-17水平与中性粒细胞、IL-6、IFN-γ、PCT和CRP水平呈正相关（均P＜0.05）；血清HMGB1和IL-17水平升高为重症肺炎合并呼吸衰竭患者预后的危险因素（P＜0.05），二者单独及联合预测患者预后死亡的AUC分别为0.892、0.889、0.960，联合预测价值较高(Z二者联合-HMGB1=2.319、P=0.020，Z二者联合-IL-17=2.146，P=0.032)。结论：重症肺炎合并呼吸衰竭患者血清HMGB1和IL-17水平升高，病情越严重，其水平越高，且二者血清水平对患者预后具有较高预测价值。

关键词： chimeric antigen receptor   CAR   chimeric autoantigen receptor   CAAR   hypersensitivity   allergy   autoimmunity  

摘要： Hypersensitivity reactions are dysregulated and potentially devastating immune responses, characterized by a tendency to become chronic. They target either self-proteins or harmless foreign proteins and are driven by both T and B cells. Although numerous symptomatic treatment options for hypersensitivity reactions have been established over recent decades, only a few antigen-specific, causal approaches capable of specifically targeting the pathogenic autoreactive T and/or B cells have been developed. Among these are cell-based treatment modalities involving chimeric antigen receptor (CAR)- or chimeric autoantibody-receptor (CAAR)-expressing cells. These therapies utilize B- or T-cell antigens, presented as B-cell epitopes or peptide-major histocompatibility complexes (pMHCs) to serve as bait. The latter are coupled to potent activation domains derived from the TCR/CD3 complex itself, such as the zeta or CD3 chains, as well as domains from bona fide co-stimulatory molecules (e.g., CD28, 4-1BB). Recent in vitro and in vivo studies have demonstrated the therapeutic potential of these ATMP-based strategies in eliminating autoreactive lymphocytes and alleviating hypersensitivity reactions. This systematic review provides a comprehensive overview of the current status of antigen-specific CAR and CAAR T-cell therapies, highlighting novel directions as well as the ongoing challenges within this promising research field.

关键词： macrophage   smooth Brucella   transcriptional response   key gene   bioinformatics  

摘要： Smooth Brucella are the main pathogenic bacteria that threaten human health and food safety. The early stage of smooth Brucella and macrophage interaction is an important phase, and smooth Brucella species elicit a dramatic transcriptional response in infected macrophages. However, the key transcriptional events are still obscure. This study aimed to identify key candidate response pathways and genes in macrophages infected with smooth Brucella at the early interaction stage. Three gene expression profiles including GSE21117, GSE5202, and GSE8385 were retrieved from the NCBI GEO database, and were integrated using comprehensive bioinformatics methods including gene set enrichment analysis, differentially expressed gene analysis, protein and protein interaction (PPI) network construction, and transcription factor prediction. The results showed that 16 up-regulated and 22 down-regulated pathways were identified, including six up-regulated immune-related pathways. A total of 41 up-regulated and four down-regulated genes were identified, and a PPI network including 31 nodes and 134 edges was constructed based on the interactive information of 45 dysregulated genes. A highly correlated module comprising 19 nodes and 103 edges was identified based on the topological features of the whole PPI network. Seven centrality analyses revealed that Tnf and Il1b were essential genes in the highly correlated module, and that the two essential genes were simultaneously enriched in eight significantly up-regulated pathways (including two immune-related pathways). Bcl3 was predicted as a transcription factor in the highly correlated module, and may play regulatory roles in the transcription of Tnf and Il1b genes. The present study identified Tnf and IL1b as candidate key response genes in infected macrophages at the early stage of smooth Brucella and macrophage interaction, which contributes to a deeper understanding of the early key transcriptional events in macrophages infected with

关键词： pharmacogenomics   genetic variants   TNF inhibitors   human leukocyte antigen   drug efficacy and safety  

摘要： Tumor necrosis factor alpha inhibitors (TNFi) are biologic drugs that target TNF alpha, a key pro-inflammatory cytokine, to suppress disease activity and alleviate symptoms of various autoimmune diseases, including inflammatory bowel disease. This review focuses on the five US FDA-approved TNFi including the monoclonal antibodies Infliximab, Adalimumab, Golimumab, Certolizumab pegol and the soluble TNF alpha receptor fusion protein Etanercept, with a brief mention of other available biosimilars to TNFi. The review aims to summarize the recent evidence on the pharmacokinetics, pharmacodynamics, and pharmacogenomics of TNFi with a particular focus on Human Leukocyte Antigen (HLA) variants in terms of their genetic contribution to the response to TNFi. HLA variants have been linked to heterogeneity in the efficacy and safety of TNFi among patients. Building on the summarized evidence, the last part of the review discusses the potential clinical utility of testing for pharmacogenetic variants that are linked to the response to TNFi prior to the drug prescription, and it also addresses the future directions to achieve personalized treatment for TNFi users.

关键词： biomarkers   chronic kidney disease   cytokine   difelikefalin   pruritus   CKD-aP   chronic kidney disease-associated pruritus   IL   interleukin   KOR   kappa opioid receptor   WI-NRS   Worst Itching Intensity Numerical Rating Scale  

摘要： Chronic kidney disease-associated pruritus (CKD-aP) is a distressing condition with a poorly understood pathogenesis. We investigated the relationship between itch intensity and serum levels of 20 pruritic and inflammatory markers in patients with moderate-to-severe CKD-aP. This was a retrospective analysis of data from 851 patients enrolled in two randomized phase 3 trials of difelikefalin, a selective kappa-opioid receptor agonist approved for treating moderate-to-severe CKD-aP. Itch intensity was assessed using the patient-reported Worst Itching Intensity Numerical Rating Scale (WI-NRS). Samples for marker measurement were collected at baseline (pre-treatment) and at Week 12. Multiple regression analysis revealed that baseline itch intensity correlated with a group of chemokines and other markers (CCL2, CCL17, CCL22, CCL27, CXCL10, CXCL11, IFNγ, IL-2, IL-31, NGF). At Week 12, levels of 10 markers (CCL2, CCL22, CXCL2, CXCL10, IFNγ, IL 2RA, IL-31, NGF, TNFα, TSLP) were significantly decreased from baseline in responders to difelikefalin treatment (defined as ≥30% WI-NRS score reduction), but not in non-responders. Levels did not differ between placebo-treated responders and non-responders. The difelikefalin-associated reductions in the 10-marker group levels examined together also revealed a significant difference between the entire difelikefalin- and placebo-treated populations. These findings indicate that CKD-aP intensity is linked to systemic inflammation, potentially via a neuroimmune crosstalk mechanism. They also suggest an anti-inflammatory mechanism of action provides a significant contribution to difelikefalin’s efficacy.

关键词： electrocatalysts   PtCu nanoparticles   de-alloyed structure   nitrogen-doped carbon   identical location transmission electron microscopy   accelerated stress test   ORR  

摘要： This report introduces a high-performance bimetallic electrocatalyst for the oxygen reduction reaction (ORR) featuring a 20 wt.% platinum content. The PtCu-based catalyst combines de-alloyed nanoparticles (NPs) supported on nitrogen-doped carbon. Enhanced uniformity in NP distribution significantly boosts the catalyst performance. Nitrogen-doped carbon provides active centers for NP deposition, which is confirmed by HAADF-STEM and EDX. The PtCu/CN catalyst achieves over 5.6 times the ORR mass activity and two times the stability under pulse cycling compared to commercial Pt/C. Uniquely, the study examines bimetallic NPs and local nano-sites before and after stress testing using IL-TEM. In situ analysis of PtCu/CN microstructure revealed two primary degradation mechanisms, (i) partial dissolution of NPs and (ii) NP agglomeration, with the C-N support significantly mitigating these effects through strong NP-support interactions. The findings underscore the prospects of bimetallic PtCu catalysts with nitrogen-doped support by showcasing exceptional ORR activity and durability.

关键词： HUVECs   pesticides   inflammatory pathway   immunofluorescence   RT-PCR   SEM   ROS  

摘要： Barrier function regulation, angiogenic potential, and immune response modulation are only a few of the many roles of the vascular system that nowadays represent one of the main targets for environmental pollutants, in particular, pesticides. We have used human umbilical vein endothelial cells (HUVECs) as an in vitro model to investigate the effects of pesticides on the activation of the NALP3-CASP1-IL-1 beta inflammatory pathway using real time PCR (RT-PCR) and immunofluorescence investigations, reactive oxygen species (ROS) generation, and morphological alterations with scanning electron microscopy (SEM) analysis. Our findings offer a comprehensive evaluation of the cellular and molecular damage induced by pesticide exposure and show strong inflammasome activation. They indicate that these chemicals may initiate necroptosis and drive prolonged inflammation in endothelial cells. This study provides crucial insights into how pesticides contribute to endothelial dysfunction, highlighting the need for further investigation into their inflammatory and immune-modulatory effects on vascular health.

关键词： Arecoline   Oral cancer   Network toxicology   TP53   TNF   IL6   CASP3  

摘要： The IARC classified betel nut as Group 1 carcinogen (2004) and arecoline as Group 2B carcinogen (2020), with approximately one-third of global oral cancer cases attributed to smokeless tobacco or betel nut consumption. While current evidence establishes an association between arecoline and oral cancer, the underlying molecular mechanisms remain complex and poorly elucidated. This study employs network toxicology integrated with molecular docking techniques to systematically investigate the potential molecular pathogenesis of arecoline-induced oral cancer, aiming to provide novel insights for targeted therapeutic strategies. The SMILES structure of arecoline was retrieved from PubChem for foundational data preparation. Toxicity profiling was conducted using ProTox-3.0 and ADMETlab databases. Potential targets of arecoline were identified via STITCH and SwissTargetPrediction. Oral cancer-related targets were collated from GeneCards, OMIM, and TTD. Intersection analysis between arecoline targets and oral cancer-associated targets was performed to identify shared targets, which were further utilized to construct compound-target regulatory network and subjected to PPI, GO, and KEGG analyses. Core targets driving oral cancer were screened using the cytoHubba plugin. Then, the correlation between core targets and immune cell infiltration in oral cancer was explored, and molecular docking validated the binding affinity of arecoline to core targets. Finally, Gromacs 2022.3 software was used to simulate the molecular dynamics of the complexes obtained by molecular docking for 100 ns. Using the STITCH and SwissTargetPrediction databases, a total of 46 potential targets of arecoline were identified. Concurrently, 2,375 oral cancer-related targets were retrieved from GeneCards, OMIM, and TTD. Intersection analysis of these two target sets yielded 26 overlapping targets. PPI analysis revealed that TP53, IL6, SNAI1, and CASP3 occupied central positions in the network, exhibiting e